Neutron capture therapies are two-part radiation therapies relying on the selective loading of tumor cells with a pharmaceutical containing .sup.10 B (or other isotopes with high neutron capture cross-sections) and subsequent tissue irradiation with thermal neutrons. Boron is nonradioactive until a thermal neutron is captured causing a .sup.10 B(n,.alpha.).sup.7 Li fission reaction. The resulting alpha and lithium particles are high in energy (sharing 2.3 MeV), LET, and RBE, and travel less than 10 microns in tissue. These features lead to selective tumor-cell killing provided the .sup.10 B-containing pharmaceutical localizes well in the tumor. Other nuclides with high neutron capture cross-sections could also be used.
An external beam of thermal neutrons will be able to treat .sup.10 B-loaded tumors located at, or close to, the tissue surface. However, thermal neutrons are attenuated very rapidly in tissue. The need to provide a high flux of thermal neutrons at greater depths can be realized if a neutron beam with higher than thermal energy is used. The abundance of light hydrogen in tissue allows the higher energy ("epithermal") neutrons to be moderated through elastic collisions.
As the energy of the external neutron beam is increased, the thermal neutron flux at a given depth is increased. However, if the energy of the epithermal neutron beam is too high, the skin sparing due to 1/v reduction in the capture cross-section of .sup.1 H and .sup.14 N (and any .sup.10 B located in healthy tissues near the surface) will be offset by an unacceptably large surface dose created by protons recoiling from collisions with fast neutrons. A trade-off must be realized, then, between maximizing the thermal neutron flux at depth, and minimizing the dose to healthy tissue (particularly at the surface). The question of which energy (or range of energies) results in the optimum trade-off for a particular neutron capture therapy application is important in the development of epithermal neutrons.
Sources of energetic neutrons include nuclear reactors and particle accelerators in which energetic charged particles bombard one or more of a variety of target materials. A number of reactions have been investigated as potential sources of epithermal neutrons including .sup.7 Li(p,n) at energies between 1.88 and 3.5 MeV, and .sup.9 Be(p,n) at energies between 1.8 and 4.1 MeV. These reactions are endothermic and require high power accelerators to generate sufficiently intense neutron beams. An alternate approach is to make use of the exothermic .sup.9 Be(d,n) reaction. This reaction generates large quantities of high energy neutrons unless the deuteron bombarding energy is set below 2.0 MeV. It is then possible to design spectrum shifters (moderator/reflector assemblies) such that the final epithermal neutron beam from the .sup.9 Be(d,n) reaction is suitable for clinical use in the treatment of deep-seated tumors (Boron Neutron Capture Therapy) or rheumatoid arthritis (Boron Neutron Capture Synovectomy).
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints characterized by inflammation of the synovium, the membrane which lines the joint capsule. RA afflicts approximately 1% of the population of the United States and is three times as prevalent among women as men. Synovial inflammation is the primary cause of pain and physical disability in RA sufferers, with the most commonly affected joints being the knee (in 56% of the patients) and the metacarpophalangeal joints (in 87% of patients). If left untreated, chronic synovial inflammation eventually leads to the formation of pannus and the enzymatic destruction of the joint cartilage. Although the causes of cartilage destruction are not completely understood it is well established that the proliferation of inflamed synovium in the joint plays an important role.
The treatment of RA usually involves the use of various drug regimens aimed at reducing the synovial inflammation. While these therapies can satisfactorily control the symptoms of RA in a majority of patients, destruction of the joint still proceeds and eventually joint replacement becomes the only alternative.
Synovectomy, the removal or ablation of the inflamed membrane, has been shown to alleviate the symptoms of rheumatoid arthritis for periods of up to 5 years and may also slow the progress of cartilage and bone destruction. In surgical synovectomy, the membrane is excised either by open surgery or arthroscopy. These procedures have several serious drawbacks. First, the complex geometry of the joint space makes it virtually impossible to remove all the disease synovium. Second, the attendant dangers of surgery are always present, including infection and the risk of anesthesia. Finally, prolonged hospitalization and rehabilitation are often required, making this treatment both expensive and inconvenient for the patient.
Radiation synovectomy is presently the only alternative to surgical synovectomy. In radiation synovectomy, a beta-emitting radionuclide is injected directly into the joint space. Typically, the radionuclide is incorporated into a colloid which is rapidly taken up by the synovial lining through phagocytosis and delivers a lethal radiation dose (approximately 10,000 rad) to the synovium within a period of hours to weeks. Because the entire surface of the synovium is exposed to the radiopharmaceutical, there is a high likelihood of complete destruction of the diseased membrane. The synovium is typically several millimeters thick so beta-emitters which deposit their energy within 1-10 mm in tissue are used, including .sup.198 Au, .sup.32 P, .sup.90 Y, etc.
The efficacy of radiation synovectomy has been shown to be similar to that of surgical synovectomy, with reported success rates of up to 80% for the treatment of early-stage RA of the knee. Radiation synovectomy is much less invasive than surgical synovectomy: the radionuclide is usually administered in a single dose under local anesthetic and, in the case of the shorter-lived radionuclides such as .sup.165 Dy, no hospital stay is required. In addition, the required rehabilitation time is usually minimal. However, despite its many advantages over surgical synovectomy, radiation synovectomy has not gained acceptance in the United States because of the inherent dangers of internal radioisotope therapy.
The primary drawback of radiation synovectomy is the delivery of radiation dose to non-target organs due to leakage of the radionuclide-containing compound from the joint cavity. Investigators using colloids of .sup.198 Au and .sup.90 Y have reported leakage of a few percent up to as much as 60% of the injected dose. This is leakage has been shown to result in unacceptable radiation exposure to the liver, spleen, and lymphatic system.